Abstract

Human prostatic epithelial cells constitutively secrete prostate-specific antigen (PSA), a kallikrein-like serine protease, which is a normal component of the seminal plasma. PSA is currently used as a specific diagnostic marker for the early detection of prostate cancer. We demonstrate that PSA degrades extracellular matrix glycoproteins fibronectin and laminin and, thus, may facilitate invasion by prostate cancer cells. Blocking PSA proteolytic activity with PSA-specific mAb results in a dose-dependent decrease in vitro in the invasion of the reconstituted basement membrane Matrigel by LNCaP human prostate carcinoma cells which secrete high levels of PSA. A novel PSA-SDS-PAGE zymography method for the detection of matrix degrading ability of PSA is also described. We propose that: (a) because of the dysplastic cellular disorganization in early neoplastic lesions called prostatic intraepithelial neoplasia (PIN), PSA may be secreted not only at the luminal end but also, abnormally, at the cell-basement membrane interface, causing matrix degradation and facilitating invasion; and (b) PSA, along with urokinase, another serine protease secreted by prostatic epithelium, may be involved in the proteolytic cascade during prostate cancer invasion and metastasis. The discovery of the extracellular matrix degrading ability of PSA not only makes it a marker for early detection but also a target for prevention and intervention in prostate cancer.